The goal of this project is to transform the research efforts in capillary electrophoresis into an operational system for large scale DNA sequencing. To this end, we will construct a 96 capillary array instrument for large scale DNA sequencing. The instrument will be based on a prototype 12 capillary unit currently under construction. Special features will be (l) replaceable sieving matrix with automatic replacement after each run; (2) automated clean-up procedures of sequencing reactions based on electrofiltration, with reuse of the template; (3) accommodation for modular primer walking using a hexamer oligonucleotide library and other sequencing strategies; (4) new signal processing data analysis based on signal recognition principles from digital communications to extend read lengths and to provide for improved confidence levels on base calling. Improved estimations of base calling confidences will be of value in sequence assembly and finishing. The instrument will allow simple modification to change sequencing strategies and dye chemistries and have no moving parts. New capillary coatings should increase substantially the ruggedness of the capillary separation of Sanger reaction products. The instrument will be tested on samples provided by the GESTEC at Washington University under the direction of Dr. Waterston. With improvements in separation speed and using 96 capillaries, we expect to increase sequencing throughput by at least one order of magnitude over the recently introduced ABI 377 slab gel sequencer. In addition, substantial reductions in the cost per base are anticipated.